Discovery of human cell selective effector molecules using single cell multiplexed activity metabolomics.
David C EarlP Brent FerrellNalin LeelatianJordan T FroeseBenjamin J ReismanJonathan Michael IrishBrian O BachmannPublished in: Nature communications (2018)
Discovering bioactive metabolites within a metabolome is challenging because there is generally little foreknowledge of metabolite molecular and cell-targeting activities. Here, single-cell response profiles and primary human tissue comprise a response platform used to discover novel microbial metabolites with cell-type-selective effector properties in untargeted metabolomic inventories. Metabolites display diverse effector mechanisms, including targeting protein synthesis, cell cycle status, DNA damage repair, necrosis, apoptosis, or phosphoprotein signaling. Arrayed metabolites are tested against acute myeloid leukemia patient bone marrow and molecules that specifically targeted blast cells or nonleukemic immune cell subsets within the same tissue biopsy are revealed. Cell-targeting polyketides are identified in extracts from biosynthetically prolific bacteria, including a previously unreported leukemia blast-targeting anthracycline and a polyene macrolactam that alternates between targeting blasts or nonmalignant cells by way of light-triggered photochemical isomerization. High-resolution cell profiling with mass cytometry confirms response mechanisms and is used to validate initial observations.
Keyphrases
- single cell
- rna seq
- high throughput
- cell cycle
- bone marrow
- cancer therapy
- acute myeloid leukemia
- dna damage
- cell cycle arrest
- ms ms
- high resolution
- mass spectrometry
- endothelial cells
- induced apoptosis
- oxidative stress
- cell therapy
- cell proliferation
- regulatory t cells
- dendritic cells
- acute lymphoblastic leukemia
- microbial community
- case report
- small molecule
- mesenchymal stem cells
- type iii
- simultaneous determination
- allogeneic hematopoietic stem cell transplantation
- pluripotent stem cells
- high resolution mass spectrometry